PROJECT SUMMARY/ABSTRACT: Hypersensitivity pneumonitis (HP) is an immunologically mediated form of lung disease, resulting from inhalational exposure to a large variety of antigens. For unknown reasons, a subgroup of patients with HP without a known inciting antigen exposure develops chronic disease with progressive pulmonary fibrosis (the leading cause of death). Accurately identifying patients at risk of disease progression is necessary for prognosis and therapy. The objective of this proposal is to refine our current clinical risk stratification by identifying and validating a transcriptomic signature from peripheral blood mononuclear cells in patients with chronic HP that is predictive of disease progression. We hypothesize that the clinical course of chronic HP is associated with a peripheral blood gene expression signature of risk that can be used to refine the prognosis and predict the clinical outcome. Guided by strong preliminary data, this hypothesis will be tested by two specific aims: i) Establish transcriptomic signatures at time of initial presentation in peripheral blood mononuclear cells from patients with chronic HP in a Discovery cohort and then validate the signature in an independent chronic HP replication cohort; and ii) Establish a time-course transcriptomic profile predictive of disease progression in the Discovery cohort and validate the signature profile in the independent chronic HP replication cohort. pursuing The proposed research is significant because it will provide the knowledge that will enhance our ability to predict disease progression, a level of prognostication which is not possible with current clinical measures alone. Relevance to Public Health: This is an important and under-investigated area that has the potential to fundamentally advance our understanding of the pathobiology of disease progression and provide the groundwork to define molecular targets relevant to chronic HP disease progression.